Cilostazol preserves CA1 hippocampus and enhances generation of immature neuroblasts in dentate gyrus after transient forebrain ischemia in rats.
In the present study, cerebral ischemia was induced by a 10 min transient bilateral common carotid artery occlusion in rats combined with arterial blood pressure lowering to 37-42 mm Hg during occlusion. When histologically evaluated at 7 and 28 days after the forebrain ischemia (DAI) by staining with cresyl violet and Fluoro-Jade, the hippocampal CA1 region was most prominently damaged. At 7 DAI, treatment with cilostazol (60 mg/kg/day, orally) significantly reduced the neuronal damage in the CA1 region. The number of surviving neurons, visualized by NeuN immunostaining, in the CA1 region significantly increased at 7 and 28 DAI in the cilostazol-treated groups. To elucidate whether cilostazol enhances hippocampal neurogenesis after ischemia, we planned a co-labeling study using 5-bromo-2'-deoxyuridine (BrdU), NeuN (a marker for mature neurons) and doublecortin (DCX) (a marker for immature migratory neuroblasts). Double immunofluorescence staining at 7 DAI showed that cilostazol significantly increased the immunoreactivities of both DCX and phosphorylated cAMP-response element-binding protein (CREB) in the dentate gyrus that was co-expressed with BrdU. These results suggest that cilostazol has dual beneficial effects preserving the CA1 hippocampal region and promoting the generation of immature migratory neuroblasts in the dentate gyrus by upregulation of CREB phosphorylation after transient forebrain ischemia.
Lee
Jeong Hyun
JH
Department of Pharmacology, College of Medicine, Pusan National University, Busan, Republic of Korea.
Shin
Hwa Kyoung
HK
Park
So Youn
SY
Kim
Chi Dae
CD
Lee
Won Suk
WS
Hong
Ki Whan
KW
D000704:Analysis of Variance; D000818:Animals; D002545:Brain Ischemia / Q000209:etiology / Q000473:pathology*; D001973:Bromodeoxyuridine / Q000378:metabolism; D002340:Carotid Artery Diseases / Q000150:complications; D002470:Cell Survival / Q000187:drug effects; D000077407:Cilostazol; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D005452:Fluoresceins; D006624:Hippocampus / Q000473:pathology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D009479:Neuropeptides / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009930:Organic Chemicals; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D013777:Tetrazoles / Q000627:therapeutic use*; D013997:Time Factors
D017362:Cyclic AMP Response Element-Binding Protein; C000714848:Dcx protein, rat; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D005452:Fluoresceins; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D018696:Neuroprotective Agents; D009930:Organic Chemicals; D013777:Tetrazoles; C435731:fluoro jade; D010751:Phosphopyruvate Hydratase; D001973:Bromodeoxyuridine; D000077407:Cilostazol